Development of BBB-permeable SUMO1 small molecule degraders for glioblastoma therapy.

开发用于胶质母细胞瘤治疗的 BBB 渗透性 SUMO1 小分子降解剂。

• 批准号: 10580075
• 负责人: CHUNHAI Charlie HAO
• 金额: $ 46.54万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580075
• 关键词: ABCB1 gene; Adverse effects; Antineoplastic Agents; Binding; Binding Proteins; Biological Assay; Biological Availability; Biological Products; Brain; Brain Neoplasms; CRISPR/Cas technology; CUL1 gene; Cells; Chemicals; Chemotherapy and/or radiation; Clinical Management; Clinical Treatment; Clinical Trials; Complex; Cytoplasm; Development; Diagnosis; Dose; Drug Kinetics; Drug Targeting; Excretory function; Formulation; Glioblastoma; Guidelines; Human; In Vitro; Knock-out; Lead; Libraries; Malignant Neoplasms; Metabolic; Metabolism; Modeling; Modification; Molecular; National Cancer Institute; Neurosphere; Oncoproteins; Operative Surgical Procedures; Oral; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacotherapy; Phase; Physiological; Primary Brain Neoplasms; Proliferating; Property; Proteins; Proteomics; Rodent; Safety; Small Ubiquitin-Related Modifier Proteins; Solubility; Specificity; Structure-Activity Relationship; Technology; Testing; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; Ubiquitin; Ubiquitination; United States National Institutes of Health; Western Blotting; Xenograft procedure; absorption; analog; anticancer activity; blood-brain barrier permeabilization; chemotherapy; computational chemistry; counterscreen; curative treatments; design; drug discovery; genome-wide; improved; in vivo; lead optimization; lead series; monolayer; novel; novel anticancer drug; novel therapeutics; patient derived xenograft model; phase I trial; preclinical development; preclinical efficacy; preclinical safety; preclinical toxicity; rational design; recruit; scaffold; screening; self-renewal; small molecule; standard of care; stem cells; success; synergism; temozolomide; tumorigenesis; ubiquitin-protein ligase

Project Summary/Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor with the median survival of 9.7 months. The current standard of care treatment involves a combination of surgery, chemotherapy and radiation but only improve the median survival up to 14 months. Challenges in discovery of therapeutics for GBM include identifying drug targets and discovering therapeutics that are blood brain barrier (BBB) permeable. To meet the challenges, we have identified small ubiquitin-related modifier 1 (SUMO1) as an oncoprotein that drives the self-renewal and tumorigenesis of GBM stem cells. We have designed GBM cell-based SUMO1 assay, screened the compounds library provided by the National Cancer Institute, and identified the hit compound as the first small molecule degrader that induces SUMO1 ubiquitination and degradation in GBM cells. Structure-activity relationship (SAR) studies around the hit-derived analogs have generated three scaffolds of lead compounds with improved potency and an excellent BBB permeability. Using GBM stem cell-enriched neurospheres and derived xenografts, we have shown that the lead compounds are more effective in treatment of GBM than the standard chemotherapy temozolomide (TMZ). In this R01 project, we will optimize our lead series with the aim of identifying more potent, orally bioavailable and BBB-permeable SUMO1 degraders that will have the preclinical efficacy, safety, and pharmacokinetic properties predicting it be enable full exploration in clinical treatment of GBM. To achieve this objective, we will leverage our computational chemistry technology to assist the design of novel compounds with BBB permeability and drug-like properties through chemical modifications of our lead series in Aim 1. Each of compounds will be rationally designed, synthesized and assessed in our established compound testing funnel for their activity and target selectivity in SUMO1 degradation. Compounds that meet our criteria for success will be selected for in vitro solubility, permeability, absorption, distribution, metabolism, and excretion assessment and prioritized for the anticancer activity against GBM stem cell-enriched neurospheres. In Aim 2, the leading compounds selected from the studies of Aim 1 will be evaluated for their pharmacokinetic properties to determine oral bioavailability and BBB permeability. Selected compounds will be assessed for in vivo target engagement and therapeutic efficacy in treatment of patient derived xenograft GBM models. The optimized lead compounds selected from the studies in Aim 2 will be evaluated for their toxicology, safety pharmacology and oral formulation in Aim 3. The milestone of this project is to select optimized lead compound(s) for advancement into preclinical development phase, investigative new drug-enabling studies and phase I trials in treatment of GMB patients.

项目总结/摘要 胶质母细胞瘤（GBM）是最常见和致命的原发性脑肿瘤，中位生存期为9.7个月。 目前的标准治疗涉及手术、化疗和放疗的组合，但仅限于 将中位生存期延长至14个月。发现GBM治疗剂的挑战包括鉴定 药物靶点和发现血脑屏障（BBB）可渗透的治疗方法。为了迎接挑战， 我们已经鉴定出小泛素相关修饰物1（SUMO 1）是一种驱动自我更新的癌蛋白， GBM干细胞的肿瘤发生。我们设计了以GBM细胞为基础的SUMO 1检测方法， 由国家癌症研究所提供的库，并确定了命中化合物作为第一个小分子 在GBM细胞中诱导SUMO 1泛素化和降解的降解剂。构效关系（SAR） 围绕hit衍生类似物的研究已经产生了三种具有改进效力的先导化合物的支架 和优异的BBB渗透性。使用富含GBM干细胞的神经球和衍生的异种移植物，我们 已经表明先导化合物在治疗GBM方面比标准化疗更有效 替莫唑胺（TMZ）。在这个R 01项目中，我们将优化我们的铅系列，目的是识别更有效的， 口服生物可利用的和BBB可渗透的SUMO 1降解剂，将具有临床前疗效、安全性和 药代动力学特性预测其在GBM临床治疗中的应用前景。实现这一 目标，我们将利用我们的计算化学技术，以协助设计新的化合物， BBB渗透性和药物样性质通过化学修饰我们的铅系列在目的1。中的每 化合物将在我们建立的化合物测试漏斗中进行合理的设计、合成和评估 它们在SUMO 1降解中的活性和靶标选择性。符合我们成功标准的化合物将 选择用于体外溶解度、渗透性、吸收、分布、代谢和排泄评估 并优先考虑对富含GBM干细胞的神经球的抗癌活性。在目标2中，领先的 将评价从目标1的研究中选择的化合物的药代动力学性质，以确定 口服生物利用度和BBB渗透性。将评估所选化合物的体内靶向结合 以及在治疗患者来源的异种移植GBM模型中的治疗功效。优化的先导化合物 从目标2中的研究中选择的药物，将对其毒理学、安全药理学和口服制剂进行评价 目标3。该项目的里程碑是选择优化的先导化合物，以推进临床前研究。 开发阶段，调查性新药研究和治疗GMB患者的I期试验。